Plasmodium falciparum-infected erythrocytes induce granzyme B by NK cells through expression of host-Hsp70.
Plasmodium falciparum-infected erythrocytes induce granzyme B by NK cells through expression of host-Hsp70.
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DOI：
10.1371/journal.pone.0033774
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Esen M
中科院分区：
文献类型：
--
作者：
Böttger E;Multhoff G;Kun JF;Esen M
在对恶性疟原虫感染的红细胞 (iRBC) 的早期免疫反应中，自然杀伤 (NK) 细胞被激活，这表明其在先天抗寄生虫免疫中发挥着重要作用。然而，目前尚不清楚 NK 细胞是否直接识别 iRBC，或者 NK 细胞的刺激是否主要依赖于辅助细胞通过细胞间接触或可溶性因子激活信号。在本研究中，我们研究了膜结合宿主热休克蛋白 (Hsp) 70 在触发来自从未接触过疟疾的供体的 NK 细胞或细胞系 NK92 针对 iRBC 的细胞毒性方面的影响。通过流式细胞术和免疫印迹评估 iRBC 上的 Hsp70 和 HLA-E 膜表达以及潜在的活化 NK 细胞受体（NKG2C、CD94）。通过蛋白质印迹、RT-PCR 和 ELISPOT 分析确定，在与 iRBC 接触后，未刺激和 Hsp70 肽 (TKD) 预刺激的 NK 细胞启动颗粒酶 B (GzmB) 的产生和释放。 iRBC 的红细胞凋亡通过膜联蛋白 V 染色来测定。我们的结果表明，iRBC 膜上 Hsp70 的存在和 HLA-E 的缺失促使受感染的宿主细胞成为 NK 细胞介导的细胞毒性的靶标，寄生虫发育受损就证明了这一点。 iRBC 与 NK 细胞接触诱导 GzmB 释放。我们提出，GzmB 摄取后，iRBC 通过不依赖于穿孔素、GzmB 介导的机制发生红细胞凋亡。由于 TKD 肽可以特异性增强 NK 对 iRBC 的活性，并通过阻断 Hsp70 暴露将 NK 活性消除至基线水平，因此我们建议将 TKD 作为一种创新的免疫刺激剂，作为体内抗寄生虫治疗的辅助手段进行测试。
In the early immune response to Plasmodium falciparum-infected erythrocytes (iRBC), Natural Killer (NK) cells are activated, which suggests an important role in innate anti-parasitic immunity. However, it is not well understood whether NK cells directly recognize iRBC or whether stimulation of NK cells depends mainly on activating signals from accessory cells through cell-to-cell contact or soluble factors. In the present study, we investigated the influence of membrane-bound host Heat shock protein (Hsp) 70 in triggering cytotoxicity of NK cells from malaria-naïve donors or the cell line NK92 against iRBC. Hsp70 and HLA-E membrane expression on iRBC and potential activatory NK cell receptors (NKG2C, CD94) were assessed by flow cytometry and immunoblot. Upon contact with iRBC, Granzyme B (GzmB) production and release was initiated by unstimulated and Hsp70-peptide (TKD) pre-stimulated NK cells, as determined by Western blot, RT-PCR and ELISPOT analysis. Eryptosis of iRBC was determined by Annexin V-staining. Our results suggest that presence of Hsp70 and absence of HLA-E on the membrane of iRBC prompt the infected host cells to become targets for NK cell-mediated cytotoxicity, as evidenced by impaired parasite development. Contact of iRBC with NK cells induced release of GzmB. We propose that following GzmB uptake, iRBC undergo eryptosis via a perforin-independent, GzmB-mediated mechanism. Since NK activity toward iRBC could be specifically enhanced by TKD peptide and abrogated to baseline levels by blocking Hsp70 exposure, we propose TKD as an innovative immunostimulatory agent to be tested as an adjunct to anti-parasitic treatments in vivo.
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影响因子：
64.8
作者：
de Koning-Ward, Tania F.;Gilson, Paul R.;Boddey, Justin A.;Rug, Melanie;Smith, Brian J.;Papenfuss, Anthony T.;Sanders, Paul R.;Lundie, Rachel J.;Maier, Alexander G.;Cowman, Alan F.;Crabb, Brendan S.
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影响因子：
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32.4
作者：
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通讯作者：
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影响因子：
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作者：
KIESSLING, R;KLEIN, E;WIGZELL, H
通讯作者：
WIGZELL, H
影响因子：
20.3
作者：
Kim, Tae-Don;Lee, Su Ui;Choi, Inpyo
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Choi, Inpyo